A major challenge in photodynamic therapy (PDT) is the development of new tumor-targeting photosensitizers. The tumor-specific activation is considered to be an effective strategy for designing these photosensitizers. Herein, we describe a novel tumor-pH-responsive supramolecular photosensitizer, LDH-ZnPcS8, which is not photoactive under neutral conditions but is precisely and efficiently activated in a slightly acidic environment (pH 6.5). LDH-ZnPcS8 is prepared by using a simple coprecipitation method based on the electrostatic interaction between negatively charged octasulfonate-modified zinc(II) phthalocyanine (ZnPcS8) and cationic hydroxide layers of layered double hydroxide (LDH). The in vitro photodynamic activities of LDH-ZnPcS8 in cancer cells are dramatically enhanced relative to those of ZnPcS8 alone. The results of in vivo fluorescence imaging demonstrate that the nanohybrid is activated in tumor tissues, where it displays an excellent PDT effect resulting in 95.3% tumor growth inhibition. Furthermore, the minimal skin phototoxicity of LDH-ZnPcS8 highlights its high potential as a novel photosensitizer for activatable PDT.